Background Regarding Corticosteroids
Depending on the mode of administration, corticosteroids can be used to treat, for example, corticosteroid-responsive diseases of the upper and lower airway passages and lungs, such as seasonal (e.g., hay fever) or perennial rhinitis, which are characterized by seasonal or perennial sneezing, rhinorrhea, nasal congestion, pruritis and eye itching, redness and tearing, and nonallergic (vasomotor) rhinitis (i.e., eosinophilic nonallergic rhinitis which is found in patients with negative skin tests and those who have numerous eosinophils in their nasal secretions). The term “allergic rhinitis” as used herein includes any allergic reaction of the nasal mucosa.
Corticosteroids (Glucocorticosteroids) have been shown to be effective for the maintenance treatment of asthma as a prophylactic therapy, for the management of the nasal symptoms of seasonal and perennial allergic and nonallergic rhinitis in adults and pediatric patients, and for the relief of the signs and symptoms of seasonal allergic conjunctivitis.
Glucocorticosteroid formulations have been designed for intranasal delivery and also as formulations designed for inhaled delivery to the lung via a suspension of particles in a propellant or by direct inhalation of particles in the solid form.
Intranasal delivery of corticosteroids is usually accomplished by actuation of a metered dose device containing a suspension of colloidal/microcrystalline particles. These particles are generally above 1 micron in size. Several issues in formulation intranasal corticosteroids involve homogeneity, irritation, taste, stability, preservatives as well as limited types of ingredients and amounts approved for intranasal use as one does not want irritation or toxicity to the mucosal lining in the nose or to affect normal ciliary action in the nose or impair any sense of smell or taste.
Delivery of drugs to the nasal mucosa can also be accomplished with aqueous, propellant-based, or dry powder formulations. However, absorption of poorly soluble drugs can be problematic because of mucociliary clearance which transports deposited particles from the nasal mucosa to the throat where they are swallowed. Complete clearance generally occurs within about 15-20 minutes. Thus, poorly soluble drugs which do not dissolve within this time frame are unavailable for either local or systemic activity.
Other issues of current marketed glucocorticosteroid formulations involve systemic exposure to some corticosteroids which may lead to unwanted steroidal side-effects. Also, the onset of action is not immediate and may take several days to achieve full efficacy. This is especially important in allergic rhinitis where quick relief from allergic symptoms is desired. If these issues can be resolved, this type of treatment would be safer and more efficacious.
A representative example of a corticosteroid currently in use is mometasone furoate monohydrate: Mometasone furoate is described and claimed in U.S. Pat. Nos. 5,837,699; 6,127,353; and 6,723,713 (to Schering Corporation), the disclosures of which are hereby incorporated by reference. The compound has anti-inflammatory activity and is particularly useful for the treatment of respiratory disorders, particularly upper airway diseases.
Depending on the mode of administration, mometasone furoate can be used to treat, for example, corticosteroid-responsive diseases of the upper and lower airway passages and lungs, such as seasonal (e.g., hay fever) or perennial rhinitis, which are characterized by seasonal or perennial sneezing, rhinorrhea, nasal congestion, pruritis and eye itching, redness and tearing, and nonallergic (vasomotor) rhinitis (i.e., eosinophilic nonallergic rhinitis which is found in patients with negative skin tests and those who have numerous eosinophils in their nasal secretions). The term “allergic rhinitis” as used herein includes any allergic reaction of the nasal mucosa.
In addition, the mometasone furoate compositions described herein can be used to treat asthma, including any asthmatic condition marked by recurrent attacks of paroxysmal dyspnea (i.e., reversible obstructive airway passage disease) with wheezing due to spasmodic contraction of the bronchi. Asthmatic conditions which may be treated or prevented in accordance with this invention include allergic asthma and bronchial allergy characterized by manifestations in sensitized persons provoked by a variety of factors including exercise, especially vigorous exercise (exercise induced bronchospasm), irritant particles (e.g., pollen, dust, cotton, dander, etc.), as well as mild to moderate asthma, chronic asthma, severe chronic asthma, severe and unstable asthma, nocturnal
Mometasone furoate is also approved for topical dermatologic use to treat inflammatory and/or pruritic manifestations of corticosteroid-responsive dermatoses. Thus, like other topical corticosteroids, mometasone furoate has anti-inflammatory, antipruritic, and vasoconstrictive properties.
Mometasone furoate is marketed as NASONEX® Nasal Spray (Shering Corporation) and mometasone furoate monohydrate is the active component in this commercial product. NASONEX® Nasal Spray, 50 mcg is a metered-dose, manual pump spray unit containing an aqueous suspension of mometasone furoate monohydrate equivalent to 0.05% w/w mometasone furoate calculated on the anhydrous basis; in an aqueous medium containing glycerin, microcrystalline cellulose and carboxymethylcellulose sodium, sodium citrate, 0.25% w/w phenylethyl alcohol, citric acid, benzalkonium chloride, and polysorbate 80. The pH is between 4.3 and 4.9. Adverse reactions from the current marketed form of mometasone furoate monohydrate include headache, viral infection, pharyngitis, eptistaxis/blood-tinged mucus, coughing, upper respiratory tract infection, dysmenorrheal, musculoskeletal pain, sinusitis and vomiting.
After initial priming (10 actuations), each actuation of the pump delivers a metered spray containing 100 mg of suspension containing mometasone furoate monohydrate equivalent to 50 mcg of mometasone furoate calculated on the anhydrous basis. NASONEX is a corticosteroid and the precise mechanism of corticosteroid action on allergic rhinitis is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation. Intranasal corticosteroids may cause a reduction in growth velocity when administered to pediatric patients.
There are several disadvantages with conventional nasal dosage forms of mometasone furoate monohydrate, including the use of benzalkonium chloride as a preservative. The presence of benzalkonium chloride limits the use of these formulations because some patients are allergic to benzalkonium chloride and other patients find the smell to be unpleasant. The onset of action in allergic rhinitis can take several days. Any formulation which can create a faster onset of action, better efficacy while not increasing systemic exposure would be highly desirable. The current marketed product does not contain salt (Nasonex®) and application of intransal corticosteroids in some isotonic media is preferred to increase tolerability.
Inhaled delivery of corticosteroid particles must be controlled for the aerodynamic particles size as targeted delivery to the lung must be optimized so the patient in need does not swallow or exhale a significant portion of the dose. Very small particles (100-200 nm) might be expected to be significantly exhaled so small inhaled corticosteroid formulations must be adjusted to have a redispersible agglomerate of smaller particles with the effective particle size of the agglomerate in the 1-4 micron range.
B. Background Regarding Nanoparticulate Corticosteroid Compositions
Several Patents and applications exist regarding the preparation of corticosteroid sub-micron (nanoparticulate) formulations. The anticipation of small particle corticosteroids compositions is that they may offer the following advantages: (1) the composition may be formulated in a dried form which readily redisperses; (2) the composition may offer a potential decrease in the frequency of dosing; (3) smaller doses of drug may be required to obtain the same pharmacological effect as compared to conventional microcrystalline or soluble forms of corticosteroids; (6) the nanoparticulate compositions may not require organic solvents or pH extremes.
Nanoparticulate compositions for cocorticosteroids are described, for example, in U.S. Pat. No. 6,264,922 for “Aerosols Containing Nanoparticulate Dispersions,” U.S. Pat. No. 5,747,001 for “Aerosols Containing Beclomethasone Nanoparticle Dispersions;” U.S. 20040208833 A1 to Hovey et al., for “Novel fluticasone formulations, U.S. Pat. No. 7,459,146v for “Stabilized Aerosol Dispersions”, US 20040057905 A1 to Wood et al., for “Nanoparticulate beclomethasone dipropionate compositions,” US 20040141925 to Bosch et al., for “Novel triamcinolone compositions,” US 20030129242 to Bosch et al., for “Sterile filtered nanoparticulate formulations of budesonide and beclomethasone having tyloxapol as a surface stabilizer”, US 20070178051 to Pruitt et al., for “Sterilized Nanoparticulate Glucocorticosteroid Formulations”, WO/2007/064912 to Hovey et al. for “ Mometasone Compositions and Methods of Making and Using the Same”.
One way to provide for a small “nano” particle drug formulation is to form a submicron particle liquid formulation, e.g., nanosuspension. When dealing with nanosuspensions, the less water soluble and more lipophilic the drug, the more difficult it is to obtain a stable small particle “nanosuspension” in polar solvents like water. Particle growth (Otswald Ripening) and aggregation must be minimized in nanoparticulate compositions if the benefit of small particle formulations is to be realized.
Preparation of nanosuspensions is known in the art. The preparation of small particle pharmaceutical compositions (effective particle size (D50) of less than 500 nm) have been described since 1988 (H. Steffen BT Gattefosse No. 81, 1988 pp. 45-53; U.S. Pat. No. 4,540,602 (Motoyama, et al.); and U.S. Pat. No. 5,145,684 (Liversidge, et al.)). These submicron (nanoparticulate) compositions all describe using non-crosslinked excipients associated with the surface of the small particle to stabilize the composition from significant particle size growth and/or agglomeration. Generally, surface stabilizers fall into two categories: non-ionic (also called steric stabilizers or modifiers) and ionic stabilizers. The most common non-ionic stabilizers are excipients which are contained in classes known as binders, fillers, surfactants and wetting agents. Limited examples of non-ionic surface stabilizers are hydroxypropylmethyl cellulose, polyvinylpyrrolidone, Plasdone, polyvinyl alcohol, Pluronics, Tweens and Polyethyleneglycols (PEGs). A subset of surface stabilizers commonly used is ionic in nature. These ionic surface stabilizers tend to fall into the class of excipients which are typically used as surfactants and wetting agents. Ionic stabilizers used in the prior art are typically organic molecules bearing an ionic bond such that the molecule is essentially fully charged in the formulation. The two most described ionic surface stabilizers are the long chain sulfonic acid salts sodium lauryl sulfate and dioctyl sodium sulfosuccinate (DOSS). Broad ranges for all surface stabilizers have been claimed in U.S. Pat. No. 5,145,684 (the '684 patent) ranging from 0.1% to 90% by weight of the composition. Typically, one adds 20%-150% (wt % of drug) of a nonionic surface stabilizer and 0.2%-5% of an ionic surface stabilizer (wt % of drug) to achieve maximal particle size stabilization from these surface stabilizers. Since 1988, many papers and patents have published relating to nanoparticulate compositions and various ways to optimize the method of manufacture, use and stability of such compositions. These surface stabilizers are diffusion controlled and the prior art teaches that one typically needs at least 15% of the steric stabilizer (w/w) based on drug to prevent particle size growth upon storage. The patent literature generally claims amounts of surface stabilizers in relation to the drug in suspension or the percent weight of the composition. Wide ranges are generally claimed for these stabilizers and little or no attention has been paid to the amount of surface stabilizers needed to stabilize nanoparticulate drugs at low or high concentrations. Corticosteroid suspensions are unusual in standard nanoparticle stabilization for several reasons. They are quite lipophilic and water insoluble creating a large potential for the drug particles to agglomerate in a polar environment such as water or physiological fluids. Corticosteroids are extremely potent drugs so the amount delivered is small and stabilization of drugs at low concentration is not generally addressed in the prior art. The amount and type of approved additives for intranasal and inhaled compositions is much more limiting than those allowed for oral administration. We have found that as one dilutes corticosteroids suspensions the amount of steric surface stabilizers (e.g. HPMC) must be increased relative to the amount of drug in the suspension to maintain stabilization of particle size upon storage. Surprisingly, once the composition is cured with a complexing agent, it can be diluted without addition of more complexing agent while the attributes of a complexed particle is maintained. This is an unexpected finding as stabilizers of small particles are considered reversible and diffusion controlled.
It would be advantageous to provide nanoparticulate formulations for corticosteroids which provide enhanced stability (storage and in physiological media), physical and chemical properties and can provide enhanced absorption in the nose or lungs to achieve an optimal balance between pharmacodynamic and side effect profiles in mammals, and dosage forms containing the same, as well as methods of making nanoparticulate drug formulations and their use in the treatment of various disorders.